Cardiac injury is associated with inflammation in geriatric COVID‐19 patients

Abstract Background Geriatric patients with coronavirus disease (COVID‐19) are at high risk of developing cardiac injury. Identifying the factors that affect high‐sensitivity cardiac troponin I may indicate the cause of cardiac injury in elderly patients, and this could hopefully assist in protecting heart function in this patient population. Methods One hundred and eighty inpatients who were admitted for COVID‐19 were screened. Patients older than 60 years were included in this study, and the clinical characteristics and laboratory results of the cohort were analyzed. The correlation between cardiac injury and clinical/laboratory variables was statistically analyzed, and further logistic regression was performed to determine how these variables influence cardiac injury in geriatric patients. Results Age (p < 0.001) significantly correlated with cardiac injury, whereas sex (p = 0.372) and coexisting diseases did not. Rising procalcitonin (p = 0.001), interleukin‐2 receptor (p < 0.001), interleukin 6 (p = 0.001), interleukin 10 (p < 0.001), tumor necrosis factor α (p = 0.001), high‐sensitivity C‐reactive protein (p = 0.001), D‐dimer (p < 0.001), white blood cells (p < 0.001), neutrophils (p = 0.001), declining lymphocytes (p < 0.001), and natural killer cells (p = 0.005) were associated with cardiac injury and showed predictive ability in the multivariate logistic regression. Conclusion Our results suggest that age and inflammatory factors influence cardiac injury in elderly patients. Interfering with inflammation in this patient population may potentially confer cardiac protection.


| INTRODUC TI ON
Since the initial outbreak of the novel coronavirus disease (COVID- 19) in December 2019, the pandemic has emerged as an unprecedented global healthcare crisis, with a total of 45,428,731 cases, including 1,185,721 deaths worldwide, as of October 31, 2020. 1 COVID-19 is caused by infection from the newly discovered, highly contagious virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 2 Severe cases can rapidly progress to a series of syndromes, such as acute respiratory distress syndrome, septic shock, multiple organ dysfunction syndrome, and even death. 3 While COVID-19 mainly affects the lungs, cardiac injury is frequently observed by monitoring the levels of high-sensitivity cardiac troponin I (hs-TnI) and is reportedly associated with worsened mortality. 4,5 Cardiovascular complications, such as malignant arrhythmia (atrial fibrillation, ventricular tachycardia, and ventricular fibrillation), myocarditis, and heart failure, all of which can be life-threatening, are common as well. 6,7 Systemic inflammation, including sepsis, can reportedly lead to an increased risk of cardiac injury. 8 On the other hand, angiotensin-converting enzyme 2 (ACE2), the essential receptor for SARS-CoV-2 invasion, is expressed in the cardiovascular system and may lead to direct cardiomyocyte infection. 9 Thus far, inflammation, hypoxia, and direct virus infection have become the major hypotheses for cardiac involvement in the general population with COVID-19. 10 However, the definite mechanism of cardiac injury during COVID-19 remains unclear. Age has been widely established as a key risk factor for infection and aggravation of COVID- 19. It has been observed that geriatric patients are at a higher risk of poor prognosis after SARS-CoV-2 infection; thus, how the virus affects the heart in these patients and how to predict cardiac injury are crucial. 11 However, studies focusing on cardiac injury in geriatric patients are limited. Hence, we performed a retrograde analysis of cardiac injury in elderly patients to determine the clinical and experimental factors related to such injuries in this population. Our study aimed to reveal the mechanism behind cardiac injury in geriatric patients with COVID-19 and predict cardiac risk.

| Study design and participants
Patients from several treatment centers in Tongji Hospital of Huazhong University of Science and Technology, Wuhan, China were enrolled in this study. All hospitalized patients who were over 60 years of age with confirmed COVID-19 diagnosis between February 8, 2020 and March 10, 2020 were included. Patients who did not undergo an hs-TnI test and had incomplete medical records were excluded. Only oral informed consent was obtained, in consideration of an emergency. Of the 180 patients screened, seven did not meet the eligibility criteria (one patient lacked the troponin test and six patients had incomplete information), and 54 patients who were younger than 60 years (youth group) were also excluded ( Figure 1). There were 27 patients in the Tnl-positive group (over the reference interval: men, 34.2 ng/ml; women 15.6 ng/ml) and 92 in the Tnl-negative group. All diagnoses were confirmed according to the World Health Organization interim guidelines. 12 All patients had previously undergone a series of tests that included high-throughput sequencing or real-time reverse transcriptase polymerase chain reaction (PCR) for nasopharyngeal and anal swabs, computed tomography scanning, and a physical examination.
This study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from the Medical Ethics

| Data collection
Clinical and laboratory test results were collected from electronic medical records and included symptom presentation (fever, cough, sputum, dyspnea, diarrhea, or chest pain), medical history (coronary heart disease [CHD], hypertension, diabetes, stroke, F I G U R E 1 Patient screening and enrollment flow chart chronic kidney disease, malignant disease, or chronic obstructive pulmonary disease), cardiac markers (hs-TnI, creatine kinase-MB [CK-MB], myoglobin, and N-terminal pro-brain natriuretic peptide [NT-proBNP]), liver function, serum ions, kidney function, complete blood cell count, arterial blood gas analysis, cytokines, immunity function, lymphocyte subsets, coagulation function, thyroid function, and ferritin levels. Two researchers transferred the data from the patient medical records to Microsoft Excel tables, which were verified by another researcher to ensure their veracity.

| Statistical analysis
Statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). Binary variables are described as frequency rates and percentages, and continuous variables are described using median and interquartile range (IQR) values. A portion of the partial continuous data were first converted to binary variables by the defined reference interval because of a difference in the reference interval between sexes. All binary variables were compared using the chi-square test and continuous variables using Spearman's rank correlation coefficient. The indicators that showed the most significant differences in the single-factor analysis were assessed by bivariate and multivariate logistic regressions. The odds ratio (OR) with a 95% confidence interval (CI) was also computed and adjusted for age and sex. For all statistical analyses, a p value < 0.05 was considered significant.

| Patient characteristics
The study population included 119 hospitalized patients over 60 years of age with a confirmed diagnosis of COVID- 19 Abbreviations: CHD, coronary heart disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease.
*p values indicate differences between TnI-positive and TnI-negative groups; p < 0.05 was considered statistically significant.

TA B L E 1 Characteristics of patients with COVID-19
However, no statistical significance was observed in symptom presentation and medical history between the TnI-positive and TnI-negative groups (Table 1).
Curve estimation analysis using hs-TnI as a continuous variable demonstrated that age correlated positively with the natural logarithm of hs-TnI levels (men, R 2 = 0.099, p = 0.022; women, R 2 = 0.292, p < 0.001). The curves for male and female patients were plotted separately ( Figure 2).

| Laboratory findings
The analysis of all laboratory tests and all reference intervals are shown in Table 2 In addition to cardiovascular markers, a wealth of data showed significant differences between the two groups. For routine hematological indices, white blood cells (WBCs) (p < 0.001) and neutrophils (p < 0.001) were higher in the positive group and lymphocytes (p < 0.001) showed a marked decline, which was attributed solely to a decline in the proportion of monocytes (p < 0.001). It is worth noting that significant differences were observed in several in-

| Factors associated with cardiac injury
We used logistic regression to examine the factors relevant to cardiac injury. Variables that were considered to be potential risk factors and showed statistical significance in the single-factor analysis were subjected to bivariate logistic regression and then adjusted for age and sex (Table 3; Figure 3). Note: All data with sex differences were converted to binary variables before analysis.
*p values indicate differences between TnI-positive and TnI-negative groups; p < .05 was considered statistically significant. Note: PCT and IL-6 were first converted to binary variables due to improper data distribution.

TA B L E 3 Logistic regression analysis of factors associated with cardiac injury
Age was analyzed as an adjustment factor, and the p value of age represented the statistical significance of age in the logistic regression model.
*p values indicate differences between TnI-positive and TnI-negative groups; p < .05 was considered statistically significant. With progress in the research on COVID-19, age has been widely accepted as a significant risk factor for infection and disease ag- Therefore, we speculated that systemic inflammation and the subsequent cytokine storm are the major risk factors for cardiac injury in patients with COVID-19.
For the excessive inflammatory response observed during COVID-19 infection, proper pharmaco-immunomodulating strategies may help improve patient condition. Several cytokine antagonists have been proven to be potential therapeutics, including IL-1 receptor antagonists, IL-6 receptor antagonists, and anti-TNF-α. 28 A clinical study by Fernández-Ruiz et al also indicated that tocilizumab, an anti-IL-6 receptor monoclonal antibody, was useful for resolving inflammation and improving patients' clinical condition. 29 Interfering with inflammatory processes should be as important as blocking virus amplification and may potentially enable cardiac protection.
The elderly patient population is greatly affected by COVID-19, and cardiac injury is common in patients with COVID-19 and is closely related to a worse prognosis, which warrants more attention to identify the related factors to continuously monitor the status of elderly patients and guide treatment. Our study suggests a potential relationship between cardiac injury and inflammation in elderly patients with COVID-19. However, the currently available evidence is inconclusive, and extensive studies on the detailed mechanism of COVID-19 and cardiac injury are needed to identify their relationship. Some limitations are inevitable at this stage of the COVID-19 outbreak. First, the sample size was not large enough; thus, we could only provide implied conclusions and contribute to future meta-analyses and systemic reviews. Second, a lack of temporal monitoring of the inflammatory factors, owing to the retrograde study design, indicates that further research is needed in the future to determine the dynamic changes between inflammatory factors and cardiac injury.

| CON CLUS IONS
Our results suggest that age and inflammatory factors influence cardiac injury in elderly patients. Interfering with inflammation in this patient population may potentially confer cardiac protection.

CO N FLI C T O F I NTE R E S T
The authors declare that they have no conflict of interest.

E TH I C A L A PPROVA L
This study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from the Medical Ethics

CO N S E NT TO PA RTI CI PATE
Only oral informed consent was obtained on consideration of emergency.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding authors upon reasonable request.